In critically ill patients with altered consciousness, continuous electroencephalogram (cEEG) improves seizure detection, but is resource-consuming compared with routine EEG (rEEG). It is also uncertain whether cEEG has an effect on outcome.To assess whether cEEG is associated with reduced mortality compared with rEEG.The pragmatic multicenter Continuous EEG Randomized Trial in Adults (CERTA) was conducted between 2017 and 2018, with follow-up of 6 months. Outcomes were assessed by interviewers blinded to interventions.The study took place at 4 tertiary hospitals in Switzerland (intensive and intermediate care units). Depending on investigators' availability, we pragmatically recruited critically ill adults having Glasgow Coma Scale scores of 11 or less or Full Outline of Responsiveness score of 12 or less, without recent seizures or status epilepticus. They had cerebral (eg, brain trauma, cardiac arrest, hemorrhage, or stroke) or noncerebral conditions (eg, toxic-metabolic or unknown etiology), and EEG was requested as part of standard care. An independent physician provided emergency informed consent.Participants were randomized 1:1 to cEEG for 30 to 48 hours vs 2 rEEGs (20 minutes each), interpreted according to standardized American Clinical Neurophysiology Society guidelines.Mortality at 6 months represented the primary outcome. Secondary outcomes included interictal and ictal features detection and change in therapy.We analyzed 364 patients (33% women; mean [SD] age, 63 [15] years). At 6 months, mortality was 89 of 182 in those with cEEG and 88 of 182 in those with rEEG (adjusted relative risk [RR], 1.02; 95% CI, 0.83-1.26; P = .85). Exploratory comparisons within subgroups stratifying patients according to age, premorbid disability, comorbidities on admission, deeper consciousness reduction, and underlying diagnoses revealed no significant effect modification. Continuous EEG was associated with increased detection of interictal features and seizures (adjusted RR, 1.26; 95% CI, 1.08-1.15; P = .004 and 3.37; 95% CI, 1.63-7.00; P = .001, respectively) and more frequent adaptations in antiseizure therapy (RR, 1.84; 95% CI, 1.12-3.00; P = .01).This pragmatic trial shows that in critically ill adults with impaired consciousness and no recent seizure, cEEG leads to increased seizure detection and modification of antiseizure treatment but is not related to improved outcome compared with repeated rEEG. Pending larger studies, rEEG may represent a valid alternative to cEEG in centers with limited resources.ClinicalTrials.gov Identifier: NCT03129438.
The first meeting on Immunity and Inflammation in Epilepsy overviewed and discussed the current knowledge in this field of experimental and clinical research with the principal aim of identifying areas of further investigations to address the still unresolved fundamental aspects. The interdisciplinary group of basic science and clinical investigators proposed preliminary answers to the identified crucial questions, as summarized in Table 1. The possible causes of brain inflammation were discussed in the frame of different epilepsy etiologies. The role of recurrent seizures per se as a cause of persistent inflammation, beyond a detectable structural insult, was highlighted. However, the identification of contributing factors to the inflammatory process and their clinical relevance are still largely unknown. The contribution of brain inflammation to hyperexcitability underlying seizures is well delineated in experimental models, although the role of inflammatory mediators in epileptogenesis requires additional studies. Aspects awaiting further investigations include: (1) the discovery and characterization of novel inflammatory molecules and pathways in multiple experimental models; (2) elucidating whether and how the inflammatory pathways so far identified converge into common molecular targets; (3) the validation of inflammatory processes described in the experimental setting in surgically resected epileptogenic tissue from epilepsies of different etiology; and (4) development of strategies to target these inflammatory factors in order to inhibit seizures and/or prevent epileptogenesis. Major challenges include exploring cellular, molecular, and genetic mechanisms that may contribute to seizures and comorbidities in immune-mediated epilepsies, and establishing disease-specific animal models, as has been done for tuberous sclerosis complex or Dravet syndrome. The elucidation of the specific bystander (association) or truly causative role of autoantibodies present in several epileptic syndromes and autoimmune disorders may also improve management (diagnosis, treatment, and long-term disease monitoring) of patients with these conditions. International disease-specific consortia will help to identify and recruit numbers of patients with the still very rare autoimmune epilepsy syndromes, sufficient to fulfil the criteria for well-designed clinical trials. Systematic collection of clinical information and biologic samples that take into account the possible immune or inflammatory aspects of the epileptic condition, the development of noninvasive techniques to image brain inflammation, and the identification of biomarkers of brain inflammation in cerebrospinal fluid (CSF) and blood will greatly improve the identification of patients who may best benefit from a specific immunosuppressant or antiinflammatory treatment. Proof-of-concept pharmacologic evidence in experimental models may contribute to the discovery of new compounds, or to the identification of drugs already used for other clinical indications (e.g., in chronic inflammatory diseases), which may be considered for prospective clinical trials for treating seizures in autoimmune-mediated epilepsies, and more in general for the treatment of seizures that are not controlled by classical antiepileptic drugs (AEDs) in nonimmune types of epilepsies. Future meetings and multidisciplinary collaborations between basic science and clinical research with translational purposes will reinforce the efforts of gaining further insights into the complex role of immunity and inflammation in epilepsy, and hopefully will encourage the development of new treatments with disease-modifying therapeutic potential. A. Vezzani and S. Rüegg thank the scientific committee, the speakers, and the discussants. They are especially grateful to the Commission of European Affair of ILAE; the American Epilepsy Society; UCB Pharma, Basel, Switzerland; Sanofi-Aventis, Milano, Italy; and Questcor Union City, CA, U.S.A. for their support, which was instrumental for the realization of this meeting. We thank Philip Schwarzkroin and Simon Shorvon for providing us the opportunity to publish the proceedings of this meeting in Epilepsia.
To determine the real-world use of rituximab in autoimmune encephalitis (AE) and to correlate rituximab treatment with the long-term outcome.
Methods
Patients with NMDA receptor (NMDAR)-AE, leucine-rich glioma-inactivated-1 (LGI1)- AE, contactin-associated protein-like-2 (CASPR2)-AE, or glutamic acid decarboxylase 65 (GAD65) disease from the GErman Network for Research on AuToimmune Encephalitis who had received at least 1 rituximab dose and a control cohort of non–rituximab-treated patients were analyzed retrospectively.
Results
Of the 358 patients, 163 (46%) received rituximab (NMDAR-AE: 57%, CASPR2-AE: 44%, LGI1-AE: 43%, and GAD65 disease: 37%). Rituximab treatment was initiated significantly earlier in NMDAR- and LGI1-AE (median: 54 and 155 days from disease onset) compared with CASPR2-AE or GAD65 disease (median: 632 and 1,209 days). Modified Rankin Scale (mRS) scores improved significantly in patients with NMDAR-AE, both with and without rituximab treatment. Although being more severely affected at baseline, rituximab-treated patients with NMDAR-AE more frequently reached independent living (mRS score ≤2) (94% vs 88%). In LGI1-AE, rituximab-treated and nontreated patients improved, whereas in CASPR2-AE, only rituximab-treated patients improved significantly. No improvement was observed in patients with GAD65 disease. A significant reduction of the relapse rate was observed in rituximab-treated patients (5% vs 13%). Detection of NMDAR antibodies was significantly associated with mRS score improvement. A favorable outcome was also observed with early treatment initiation.
Discussion
We provide real-world data on immunosuppressive treatments with a focus on rituximab treatment for patients with AE in Germany. We suggest that early and short-term rituximab therapy might be an effective and safe treatment option in most patients with NMDAR-, LGI1-, and CASPR2-AE.
Class of Evidence
This study provides Class IV evidence that rituximab is an effective treatment for some types of AE.
Acute-phase proteins, such as procalcitonin (PCT), C-reactive protein (CRP) and albumin, may relate with course and outcome in status epilepticus (SE), as seizures bring about inflammation, changes of cytokine levels and blood-brain barrier breakdown. We aimed to determine the predictive value of serum levels of PCT at SE onset for the emergence of infections and unfavorable outcome in adult patients with SE. Furthermore, we sought to compare the predictive value of PCT, CRP and albumin for death.This observational cohort study was performed in the intensive care units of the University Hospital Basel (Switzerland), a university-affiliated tertiary care center. Adult patients with SE admitted from 2005 to 2012 were included. Serum levels of PCT, CRP and albumin were assessed at SE onset. Unfavorable outcome (i.e., death and a Glasgow Outcome Score of 1 to 3) during hospital stay and mortality after 30 days were considered the primary and infections as the secondary outcome measures.In 91 SE patients, mortality was 23.1 % during hospital stay and at 30-days follow-up. Infections emerged in 30.8 % of patients. In the multivariable analysis, PCT predicted unfavorable outcome independently from possible confounders such as acute etiology, infections during SE, the Charlson Comorbidity Index, and the Status Epilepticus Severity Score (hazard ratio 1.44 per every increasing ug/L, 95 % confidence interval 1.11-1.87). Additional multivariable analysis including serum levels of PCT, CRP and albumin revealed PCT as the only biomarker independently associated with an increased hazard for unfavorable outcome. PCT levels at SE onset were not related to infections during SE.Serum PCT levels measured at SE onset are independently associated with unfavorable outcome but do not predict the emergence of infections during SE. Procalcitonin may increase the predictive value of clinical scoring systems allowing for rapid risk stratification early in the course of SE.
Imagine that your 23-year-old healthy child unexpectedly has a seizure and that seizure will not stop. You rush her to the hospital where seizures continue despite increasing doses of medications. She is intubated, transferred to the neurocritical care unit (NICU), deeply sedated, and put on continuous long-term video-EEG monitoring. Laboratory studies, CSF, and brain scanning return normal. The seizures recur as soon as the anesthetics are lowered. Testing is intensified; rare causes of seizures are searched for in vain; and the therapeutic attempts approach experimental stages. Complications increase; eventually, the patient has multiorgan failure, and the family decides to let her die. The patient obviously had new-onset refractory status epilepticus (NORSE), a—luckily rare—disorder seen by neurointensivists in NICUs of larger hospitals.
Objective To assess the association between incident Parkinson disease (PD) and subsequent incident epileptic seizures. Methods We conducted a retrospective cohort study with a nested case–control analysis using data from the U.K. Clinical Practice Research Datalink. We identified patients aged ≥40 years with an incident diagnosis of PD between 1995 and 2016 and a matched comparison group of PD‐free individuals. We calculated crude incidence rates (IRs) with 95% confidence intervals (CIs) of epileptic seizures in PD patients and the PD‐free comparison group, and corresponding crude incidence rate ratios (IRRs). In the nested case–control analysis, we calculated adjusted odds ratios (adj. ORs) of incident PD among cases with incident epileptic seizures and seizure‐free controls overall and stratified by various seizure‐provoking comorbidities. Results Among 23,086 incident PD patients and 92,343 PD‐free individuals, we identified 898 patients with incident epileptic seizures. The crude IR of epileptic seizures in PD patients was 266.7/100,000 person‐years (95% CI = 235.6–297.7), and in PD‐free individuals it was 112.4/100,000 person‐years (95% CI = 103.5–121.3; IRR = 2.37, 95% CI = 2.06–2.73). The adj. OR of epileptic seizures was 1.68 (95% CI = 1.43–1.98) in PD patients compared with PD‐free individuals. PD patients with comorbid brain disorders (adj. OR = 12.36, 95% CI = 8.74–17.48) or with > 1 seizure‐provoking comorbidity (adj. OR = 13.24, 95% CI = 10.15‐17.25) were at the highest risk of epileptic seizures compared with PD‐free individuals with no seizure‐provoking comorbidities. Interpretation This study suggests that incident PD is associated with an increased risk of incident epileptic seizures. Ann Neurol 2018;83:363–374
Abstract Background Early prognostication in patients with acute consciousness impairment is a challenging but essential task. Current prognostic guidelines vary with the underlying etiology. In particular, electroencephalography (EEG) is the most important paraclinical examination tool in patients with hypoxic ischemic encephalopathy (HIE), whereas it is not routinely used for outcome prediction in patients with traumatic brain injury (TBI). Method Data from 364 critically ill patients with acute consciousness impairment (GCS ≤ 11 or FOUR ≤ 12) of various etiologies and without recent signs of seizures from a prospective randomized trial were retrospectively analyzed. Random forest classifiers were trained using 8 visual EEG features—first alone, then in combination with clinical features—to predict survival at 6 months or favorable functional outcome (defined as cerebral performance category 1–2). Results The area under the ROC curve was 0.812 for predicting survival and 0.790 for predicting favorable outcome using EEG features. Adding clinical features did not improve the overall performance of the classifier (for survival: AUC = 0.806, p = 0.926; for favorable outcome: AUC = 0.777, p = 0.844). Survival could be predicted in all etiology groups: the AUC was 0.958 for patients with HIE, 0.955 for patients with TBI and other neurosurgical diagnoses, 0.697 for patients with metabolic, inflammatory or infectious causes for consciousness impairment and 0.695 for patients with stroke. Training the classifier separately on subgroups of patients with a given etiology (and thus using less training data) leads to poorer classification performance. Conclusions While prognostication was best for patients with HIE and TBI, our study demonstrates that similar EEG criteria can be used in patients with various causes of consciousness impairment, and that the size of the training set is more important than homogeneity of ACI etiology.
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